Processing of beta-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycancomplex

The dystroglycan complex is a membrane-spanning complex composed of two sub units, alpha- and beta -dystroglycan. alpha -dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), whereas beta -dystroglycan is an integral membrane protein which anchors a lpha -dystroglycan to the cell membrane. The dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the dystrogl ycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscu lar dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycano pathy (LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degenera tion, we investigated the proteolytic processing of the dystroglycan comple x in this study. We demonstrate that (i) a 30 kDa fragment of beta -dystrog lycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is th e product of proteolytic processing of the extracellular domain of beta -dy stroglycan by the membrane-associated matrix metalloproteinase (MMP) activi ty. Importantly, furthermore, we demonstrate that this processing disintegr ates the dystroglycan complex. Our results indicate that the processing of beta -dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in th e molecular pathogenesis of sarcoglycanopathy.